The mammalian skeleton undergoes a remarkable cycle of catabolism and anabolism during reproduction. Lactation is associated with rapid loss of a significant amount of bone, but this deficit is fully repaired after weaning. In fact, lactation and the subsequent recovery period post-weaning represent the most rapid rates of loss and gain in bone mass in the adult skeleton. Despite this fact, the mechanisms underlying the regulation of bone loss during lactation are only partly understood and nothing at all is know of the mechanisms that stimulate the anabolic response to weaning. There are many parallels between the response of bone to lactation and its response to menopause and it has been suggested that post- menopausal osteoporosis represents the inappropriate reactivation of mechanisms meant to mediate lactational bone loss. If this is true, then the mechanisms underlying the recovery of bone mass post- lactation may offer valuable clues for the treatment of post-menopausal osteoporosis. However, in order to capitalize on any such clues, we need to address our profound ignorance of the nature of the anabolic response after lactation. In order to begin to understand this process we offer an exploratory R21 application intended to generate preliminary data that will help to focus further studies on mechanisms that initiate the skeleton's response to weaning. Our proposal outlines three specific aims. The first entails studies meant to detail changes in bone mass, bone turnover, bone histology and systemic metabolism post-lactation. The second will profile changes in bone gene expression in order to identify important molecular pathways that might mediate these changes. Finally, we provide preliminary evidence to suggest that the canonical Wnt signaling pathway is activated in bone cells in response to weaning. The third aim will use a tetracycline- regulated transgenic system to inhibit Wnt signaling in bone after lactation in order to determine if this signaling pathway contributes to the initiation of the anabolic response.